Peritoneal dialysis fluid

ABSTRACT

The present invention is a sterile peritoneal dialysis fluid, including an acidic first liquid containing 60.0 to 94.0 g/L of icodextrin and 0 to 2.34 g/L of sodium chloride, and an alkaline second liquid containing an alkaline pH regulator, in which the first liquid after sterilization has a pH of 5.0 to 5.5, the second liquid after sterilization has a pH of 6.5 to 7.5, and a mixture of the first liquid and the second liquid after sterilization has a pH of 6.0 to 7.5. The present invention can provide a peritoneal dialysis fluid containing icodextrin, in which the stability of icodextrin during the heat sterilization and the subsequent storage can be improved to the maximum, and the pH of the peritoneal dialysis fluid is close to the physiological range.

TECHNICAL FIELD

The present invention relates to a peritoneal dialysis fluid containingicodextrin.

BACKGROUND ART

A peritoneal dialysis therapy which is one of the symptomatic therapiesfor renal failure has attracted attention as one of home medical cares,since the device and implement do not become large in scale as comparedwith a dialysis therapy performed through an artificial kidney and alsothere are few temporal restrictions. Many of currently-used peritonealdialysis fluids use glucose as an osmotic agent. Glucose has anadvantage of being relatively safe, and being inexpensive; however, acontinuous dehydration effect cannot be obtained because glucose has asmall molecular weight and is rapidly absorbed from the peritoneum. Fromthe above situation, an investigation of an osmotic agent that canmaintain ultrafiltration during long-term storage in place of glucosewas performed, and it has been found that icodextrin, a glucose polymer,is suitable for a peritoneal dialysis fluid.

Icodextrin is not rapidly absorbed via the peritoneum due to a largemolecular weight, and acts mainly as a colloid osmotic agent, and adehydration effect can be obtained while maintaining the osmoticpressure with blood plasma. Currently, in a peritoneal dialysis fluid inwhich icodextrin is used, a medical solution is prescribed to be in therange of pH 5.0 to 5.5 in order to prevent the decomposition andcoloring of the icodextrin.

According to a recent study, it has been reported that a peritonealdialysis fluid having such a pH substantially lowers the immunologicaldefense mechanism for a peritoneal macrophage, and increases the risk ofperitonitis against the ingress of bacteria. Furthermore, it has beenreported that in a peritoneal dialysis fluid of pH 5.0 to 5.5, damage tocultured peritoneal mesothelial cells is significantly high, and it iseffective for reducing the damage that the pH of the peritoneal dialysisfluid is 6.5 or more.

However, the pH of a peritoneal dialysis fluid has a significant impacton the stability of icodextrin; when the pH is increased withoutchanges, the icodextrin is decomposed into glucose at the time ofmanufacture or storage, the peritoneal dialysis fluid is colored by thedeterioration of the glucose, and then the product value issignificantly lowered. That is, the absorbance of 284 nm, which is anindex of 5-hydroxymethylfurfural which is a main decomposition productof glucose, is successively increased.

Therefore, as a method of increasing the pH of the peritoneal dialysisfluid while suppressing the decomposition and coloring of theicodextrin, a pharmaceutical preparation has been developed, in which anicodextrin and a liquid medicine component having high pH are separatelystored until a time for use and are aseptically mixed immediately beforeuse (Patent Literature 1).

However, requirement for the stability of peritoneal dialysis fluid andthe safety of peritoneal dialysis fluid increasingly becomeshigh-dimensional in recent years, and a development of a stableperitoneal dialysis fluid has been desired, in which a pH is in thephysiological range which does not affect on human bodies, and thedecomposition of icodextrin into glucose and the coloring of icodextrinare suitably suppressed.

CITATION LIST Patent Literatures

Patent Literature 1: Japanese Patent Application Laid-Open No.2010-150281

SUMMARY OF INVENTION Technical Problem

The present invention is to provide a peritoneal dialysis fluid, inwhich the stability of icodextrin during the heat sterilization and thesubsequent storage is improved to the maximum, and the pH of theperitoneal dialysis fluid is close to the physiological range.

Solution to Problem

The problems described above are achieved according to the followingpresent invention.

(1) The present invention is a sterile peritoneal dialysis fluid,comprising an acidic first liquid containing 60.0 to 94.0 g/L oficodextrin and 0 to 2.34 g/L of sodium chloride, and an alkaline secondliquid containing an alkaline pH regulator, in which the first liquidafter sterilization has a pH of 5.0 to 5.5, the second liquid aftersterilization has a pH of 6.5 to 7.5, and a mixture of the first liquidand the second liquid after sterilization has a pH of 6.0 to 7.5.(2) The present invention is the peritoneal dialysis fluid described inthe above (1), in which the first liquid contains neither lactic acidnor a lactate. Herein, examples of the lactate include sodium lactate,potassium lactate, and calcium lactate.(3) The present invention is the peritoneal dialysis fluid described inthe above (1) or (2), in which the alkaline pH regulator in the secondliquid contains at least one of sodium hydroxide and sodium hydrogencarbonate.(4) The present invention is the peritoneal dialysis fluid described inany one of the above (1) to (3), in which the second liquid contains atleast one of sodium chloride, lactic acid, sodium lactate, calciumchloride, and magnesium chloride.(5) The present invention is the peritoneal dialysis fluid described inany one of the above (1) to (4) being stored in a medical bag body, inwhich the bag body has a first chamber and a second chamber which areformed by separation of the inner part by a openable partition means,the first chamber having a discharge port for communicating inside andoutside the bag body, the first liquid being stored in the firstchamber, and the second liquid being stored in the second chamber.

Advantageous Effects of Invention

In the peritoneal dialysis fluid of the present invention, successiveincrease of the absorbance at 284 nm of the peritoneal dialysis fluidcan be suppressed by the separate storage of the component of theperitoneal dialysis fluid containing icodextrin and the component of thealkaline peritoneal dialysis fluid, particularly lactic acid and alactate; namely, the glucose decomposition products of icodextrin duringthe heat sterilization and the subsequent storage were largelysuppressed, and the peritoneal dialysis fluid excellent in stability canbe provided.

DESCRIPTION OF EMBODIMENTS

Hereinafter, a peritoneal dialysis fluid of the present invention willbe described in detail. The peritoneal dialysis fluid of the presentinvention mainly comprises a first liquid containing icodextrin and asecond liquid containing an alkaline pH regulator without containingicodextrin, in which the peritoneal dialysis fluid is a two-componentperitoneal dialysis fluid where the first liquid and the second liquidare mixed immediately before use, and the peritoneal dialysis fluid hasa pH of 6.0 to 7.5 after the mixture.

In the present invention, the content of the icodextrin in the firstliquid is 60.0 to 94.0 g/L, preferably 65.0 to 85.0 g/L. In a case wherethe content of the icodextrin is less than 60.0 g/L, the osmoticpressure after the mixture of the first liquid and the second liquid istoo low, and sufficient dialysis cannot be expected, and in a case wherethe content of the icodextrin contained in the first liquid exceeds 94.0g/L, it is not preferable because the content of the glucosedecomposition products becomes large. That is, according to this, theglucose decomposition products of icodextrin during the heatsterilization and the subsequent storage can be suitably suppressed, andthe peritoneal dialysis liquid stable and excellent in preservingproperty can be achieved.

The content of sodium chloride in the first liquid is 0 to 2.34 g/L,preferably 1.78 to 2.15 g/L. The sodium chloride is incorporated for thepurpose of adjusting the osmotic pressure, and when the content ofsodium chloride in the first liquid exceeds 2.34 g/L, it is notpreferable because the content of the glucose decomposition productsbecomes large.

The pH of the first liquid after sterilization is in an acidic region;specifically, it is preferable in the range of pH 4.7 to 5.5, and morepreferable in the range of pH 5.0 to 5.5. When the pH is less than 4.7or more than pH 5.5, it is not preferable because the content of theglucose decomposition products becomes large.

In addition, as needed, the pH adjustment may be performed, for example,by using hydrochloric acid, lactic acid, and the like.

Furthermore, in the present invention, the second liquid comprises atleast one of sodium hydroxide and sodium hydrogen carbonate as analkaline pH regulator. The content of the alkaline pH regulator is anamount required to adjust the pH of the peritoneal dialysis liquid to pH6.0 to 7.5, preferably pH 6.5 to 7.5 after the first liquid and secondliquid after sterilization are mixed with the addition of at least oneof a lactate and lactic acid incorporated as an alkalizing agent.

In the peritoneal dialysis fluid of the present invention, when the pHafter the mixture is less than 6.0, the immunological protectionmechanism of macrophage is lowered and damage to peritoneal mesothelialcells is high, and when the pH exceeds 7.5, an adverse effect on livingbodies is concerned.

The present invention comprises at least one of a lactate and lacticacid incorporated as an alkalizing agent, and the content is notparticularly limited, may be the same amount contained in an ordinaryperitoneal dialysis fluid as a lactate ion, and it is preferably 30 to45 mEq/L as a lactate ion after the mixture. The alkalizing agent may becontained in any one of the first liquid and the second liquid; however,it is preferably incorporated into the second liquid not containingicodextrin in view of the stability of the peritoneal dialysis fluid,for example, the suppression of the degradation of the icodextrin toglucose and the suppression of the degradation of the glucose. Examplesof the lactate include sodium lactate, potassium lactate, and calciumlactate, and preferably sodium lactate.

The peritoneal dialysis fluid of the present invention, in addition tothe components above, comprises various components contained in anordinary peritoneal dialysis fluid, i.e., a sodium ion, a calcium ion, amagnesium ion, a chloride ion, and the like. These contents may be thesame amount contained in an ordinary peritoneal dialysis fluid, and itis preferable that the sodium ion is 100 to 200 mEq/L, the calcium ionis 0 to 5 mEq/L, the magnesium ion is 0 to 5 mEq/L, and the chloride ionis 50 to 180 mEq/L after the mixture of the first liquid and the secondliquid.

The components above may be contained in any one of the first liquid andthe second liquid; however, they are preferably incorporated into thesecond liquid not containing icodextrin in view of the stability of theperitoneal dialysis fluid. Furthermore, these components may beincorporated into the peritoneal dialysis fluid of the present inventionas lactic acid, sodium lactate, sodium chloride, calcium chloride,magnesium chloride, and the like in the same manner as in an ordinaryperitoneal dialysis fluid.

In the peritoneal dialysis fluid of the present invention, the firstliquid and the second liquid are filled and packed separately into acontainer made of polypropylene, polyvinyl chloride, or the like, andsterilized, and then the first liquid and the second liquid areaseptically mixed immediately before use.

In particular, the peritoneal dialysis fluid of the present invention ispreferably separated into the first liquid and the second liquid andstored in a medical bag body having a first chamber and a second chamberwhich are formed by separation of the inner part by a openable partitionmeans, in which the first chamber has a discharge port for communicatinginside and outside the medical bag body. In this case, it is preferablethat the first liquid is stored in the first chamber, and the secondliquid is stored in the second chamber. According to this, even in acase where the first liquid and the second liquid are administeredwithout mixing by any chance, the first liquid which is osmoticallyrelatively safe can be administered.

Examples of the openable partition means include a heat seal which isable to be fractured by the liquid pressure of the stored first liquidor second liquid when one of the first chamber and the second chamber ispressed. According to this, the first liquid and the second liquid canbe easily mixed. Specific examples of the medical bag body include acontainer of MIDPELIQ (registered trademark) (manufactured by TERUMOCORPORATION).

In the present invention, examples of the sterilization method includeautoclave sterilization (high-pressure steam sterilization), and theconditions are preferably at 110 to 140° C. for 5 to 50 minutes, andspecifically at 121° C. for 30 minutes.

The peritoneal dialysis fluid of the present invention is described indetail in the above; however, the present invention is not limited tothe above, various improvements and changes may be made withoutdeparting from the scope of the invention.

EXAMPLES

Hereinafter, the present invention will be described in more detail withreference to specific examples of the present invention. However, thepresent invention should not be limited to the following Examples.

Example 1

75 g of icodextrin was dissolved into 840 mL of water for injection, anda first liquid was prepared. Furthermore, 5.35 g of sodium chloride,4.48 g of sodium lactate, 0.257 g of calcium chloride, and 0.051 g ofmagnesium chloride hexahydrate were dissolved into 160 mL of water forinjection, the pH was adjusted by sodium hydroxide, and a second liquidwas prepared. 840 mL of the first liquid and 160 mL of the second liquidwere respectively filled into a double-chamber container made ofpolypropylene (a container of MIDPELIQ (registered trademark)(manufactured by TERUMO CORPORATION)), and then the container was put ina three-side sealed bag made of polypropylene/nylon/polypropylene andwas deaeration-packaged. After that, heat sterilization (at 121° C. for30 minutes) was performed by using an autoclave, and then each pH of thefirst liquid, the second liquid, and a mixture (peritoneal dialysisfluid) was measured. The pH of the first liquid was 5.1, the pH of thesecond liquid was 7.0, and the pH of the mixture was 6.6.

Example 2

75 g of icodextrin and 1.87 g of sodium chloride were dissolved into 840mL of water for injection, and a first liquid was prepared. Furthermore,3.48 g of sodium chloride, 4.48 g of sodium lactate, 0.257 g of calciumchloride, and 0.051 g of magnesium chloride hexahydrate were dissolvedinto 160 mL of water for injection, the pH was adjusted by sodiumhydroxide, and a second liquid was prepared. 840 mL of the first liquidand 160 mL of the second liquid were filled, and heat sterilized underthe same conditions as those in Example 1, and then each pH of the firstliquid, the second liquid, and a mixture (peritoneal dialysis fluid) wasmeasured. The pH of the first liquid was 5.1, the pH of the secondliquid was 7.0, and the pH of the mixture was 6.6.

Comparative Example 1

75 g of icodextrin and 4.48 g of sodium lactate were dissolved into 840mL of water for injection, and a first liquid was prepared. Furthermore,5.35 g of sodium chloride, 0.257 g of calcium chloride dihydrate, and0.051 g of magnesium chloride hexahydrate were dissolved into 160 mL ofwater for injection, and the pH was adjusted by sodium hydroxide, and asecond liquid was prepared. 840 mL of the first liquid and 160 mL of thesecond liquid were filled, and heat sterilized under the same conditionsas those in Example 1, and then each pH of the first liquid, the secondliquid, and a mixture (peritoneal dialysis fluid) was measured. The pHof the first liquid was 5.4, the pH of the second liquid was 6.9, andthe pH of the mixture was 6.6.

Comparative Example 2

75 g of icodextrin, 5.35 g of sodium chloride, 18.3 g of calciumchloride dihydrate, 5.08 g of magnesium chloride hexahydrate, and 4.48 gof sodium lactate were dissolved into 1000 mL of water for injection andprepared. 1000 mL of the prepared liquid was filled into asingle-chamber container made of polypropylene, and then the containerwas put in a three-side sealed bag made ofpolypropylene/nylon/polypropylene and was deaeration-packaged. Afterthat, heat sterilization (at 121° C. for 30 minutes) was performed byusing an autoclave, and then the pH of the obtained peritoneal dialysisfluid was measured. The pH was 4.3.

Comparative Example 3

100 g of icodextrin was dissolved into 840 mL of water for injection,and a first liquid was prepared. Furthermore, 5.35 g of sodium chloride,4.48 g of sodium lactate, 0.257 g of calcium chloride, and 0.051 g ofmagnesium chloride hexahydrate were dissolved into 160 mL of water forinjection, the pH was adjusted by sodium hydroxide, and a second liquidwas prepared. 840 mL of the first liquid and 160 mL of the second liquidwere filled, and heat sterilized under the same conditions as those inExample 1, and then each pH of the first liquid, the second liquid, anda mixture (peritoneal dialysis fluid) was measured. The pH of the firstliquid was 4.3, the pH of the second liquid was 7.2, and the pH of themixture was 6.2.

(Time-Dependent Change Test)

As to the peritoneal dialysis fluids in Examples 1 and 2, andComparative Examples 1 to 3, time-dependent changes of the absorbance of284 nm, which is an index of 5-hydroxymethylfurfural which is a maindecomposition product of glucose, were measured. The results are shownin Tables 1 and 2. Furthermore, the peritoneal dialysis fluids inExamples 1 and 2, and Comparative Examples 1 to 3 were stored in athermostat bath at 60° C., and the mixture of the first liquid and thesecond liquid (except for Comparative Example 2) was performedimmediately before the measurement of absorbance.

TABLE 1 Example 1 Example 2 Day 0 0.087 0.089 Day 3 0.107 0.115 Day 50.120 0.125 Day 7 0.141 0.147

TABLE 2 Comparative Comparative Comparative Example 1 Example 2 Example3 Day 0 0.102 0.107 0.133 Day 3 0.121 0.244 0.155 Day 5 0.132 0.3680.289 Day 7 0.154 0.455 0.334

As shown in Tables 1 and 2, in the peritoneal dialysis fluid of thepresent invention, a peritoneal dialysis fluid having an absorbance of284 nm of less than 0.15 can be achieved after heat sterilization oreven after storing for 7 days at 60° C. by performing appropriate heatsterilization. This could not have been predicted from a conventionalart.

INDUSTRIAL APPLICABILITY

That is, as described in detail, the peritoneal dialysis fluid of thepresent invention can make the pH to be in the physiological range,maximally suppresses the decomposition of icodextrin during the heatsterilization and the subsequent storage, and thus can be industriallyapplicable as the peritoneal dialysis fluid highly excellent in thestability.

The invention claimed is:
 1. A sterile peritoneal dialysis fluid,comprising: an acidic first liquid containing 60.0 to 94.0 g/L oficodextrin and 0 to 2.34 g/L of sodium chloride, wherein the firstliquid comprises neither lactic acid nor a lactate, and an alkalinesecond liquid containing an alkaline pH regulator, wherein the firstliquid after sterilization has a pH of 5.1 to 5.5, the second liquidafter sterilization has a pH of 6.5 to 7.5, and a mixture of the firstliquid and the second liquid after sterilization has a pH of 6.0 to 7.5.2. The peritoneal dialysis fluid according to claim 1, wherein thealkaline pH regulator in the second liquid comprises at least one ofsodium hydroxide and sodium hydrogen carbonate.
 3. The peritonealdialysis fluid according to claim 1, wherein the second liquid comprisesat least one of sodium chloride, lactic acid, sodium lactate, calciumchloride and magnesium chloride.
 4. The peritoneal dialysis fluidaccording to claim 1, the first liquid containing 65.0 to 85.0 g/L oficodextrin.
 5. The peritoneal dialysis fluid according to claim 1, thefirst liquid containing 1.78 to 2.34 g/L of sodium chloride.
 6. Theperitoneal dialysis fluid according to claim 1, the first liquidcontaining 1.78 to 2.15 g/L of sodium chloride.
 7. The peritonealdialysis fluid according to claim 1, wherein the mixture of the firstliquid and the second liquid after sterilization has a pH of 6.5 to 7.5.8. The peritoneal dialysis fluid according to claim 1, wherein thealkaline regulator comprises at least one compound selected from thegroup consisting of a lactate and lactic acid.
 9. The peritonealdialysis fluid according to claim 1, wherein the mixture of the firstliquid and the second liquid comprises 100 to 200 mEq/L of sodium ion, 0to 5 mEq/L of calcium ion, 0 to 5 mEq/L of magnesium ion, and 50 to 180mEq/L of chloride ion.
 10. The peritoneal dialysis fluid according toclaim 1, wherein the second liquid after sterilization has a pH of 7.0to 7.5.